title: Prognostic significance of 2-hydroxyglutarate levels in acute myeloid leukemia in China.
abstract: The 2-hydroxyglutarate (2-HG) has been reported to result from mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes and to function as an "oncometabolite." To evaluate the clinical significance of serum 2-HG levels in hematologic malignancies, acute myeloid leukemia (AML) in particular, we analyzed this metabolite in distinct types of human leukemia and lymphoma and established the range of serum 2-HG in appropriate normal control individuals by using gas chromatograph-time-of-flight mass spectrometry. Aberrant serum 2-HG pattern was detected in the multicenter group of AML, with 62 of 367 (17%) patients having 2-HG levels above the cutoff value (2.01, log2-transformed from 4.03 μg/mL). IDH1/2 mutations occurred in 27 of 31 (87%) AML cases with very high 2-HG, but were observed only in 9 of 31 (29%) patients with moderately high 2-HG, suggesting other genetic or biochemical events may exist in causing 2-HG elevation. Indeed, glutamine-related metabolites exhibited a pattern in favor of 2-HG synthesis in the high 2-HG group. In AML patients with cytogenetically normal AML (n = 234), high 2-HG represented a negative prognostic factor in both overall survival and event-free survival. Univariate and multivariate analyses confirmed high serum 2-HG as a strong prognostic predictor independent of other clinical and molecular features. We also demonstrated distinct gene-expression/DNA methylation profiles in AML blasts with high 2-HG compared with those with normal ones, supporting a role that 2-HG plays in leukemogenesis.
authors.affiliation: State Key Laboratory of Medical Genomics, Department of Hematology, Shanghai Institute of Hematology, Rui Jin Hospital affiliated with Shanghai Jiao Tong University School of Medicine and Key Laboratory of Systems Biomedicine of Ministry of Education, Shanghai Center for Systems Biomedicine, and Department of Biostatistics, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China.
authors.forename: Jiang-Han
authors.initials: JH
authors.lastname: Wang
authors.forename: Wen-Lian
authors.initials: WL
authors.lastname: Chen
authors.forename: Jun-Min
authors.initials: JM
authors.lastname: Li
authors.forename: Song-Fang
authors.initials: SF
authors.lastname: Wu
authors.forename: Tian-Lu
authors.initials: TL
authors.lastname: Chen
authors.forename: Yong-Mei
authors.initials: YM
authors.lastname: Zhu
authors.forename: Wei-Na
authors.initials: WN
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Yun-Ping
authors.initials: YP
authors.lastname: Qiu
authors.forename: Ai-Hua
authors.initials: AH
authors.lastname: Zhao
authors.forename: Jian-Qing
authors.initials: JQ
authors.lastname: Mi
authors.forename: Jie
authors.initials: J
authors.lastname: Jin
authors.forename: Yun-Gui
authors.initials: YG
authors.lastname: Wang
authors.forename: Qiu-Ling
authors.initials: QL
authors.lastname: Ma
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.forename: De-Pei
authors.initials: DP
authors.lastname: Wu
authors.forename: Qin-Rong
authors.initials: QR
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Yan
authors.forename: Jin-Song
authors.initials: JS
authors.lastname: Yan
authors.forename: Jian-Yong
authors.initials: JY
authors.lastname: Li
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Huang
authors.forename: Bing-Shun
authors.initials: BS
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Jia
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.forename: Sai-Juan
authors.initials: SJ
authors.lastname: Chen
mesh_terms: D002681:China / Q000453:epidemiology; D019175:DNA Methylation / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D005977:Glutarates / Q000097:blood*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000097:blood* / Q000235:genetics / Q000401:mortality* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015996:Survival Rate
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: biomarker; prognosis